Autism is a severe developmental disorder afflicting about 1-2 per 1,000 individuals. While twin and family studies support significant gene involvement, the specific mode of genetic inheritance is unknown and multiplicative gene action, genetic heterogeneity, and variable expression of underlying susceptibility genes are probable. Given the unknown and complex mode of genetic inheritance in autism, success in localizing underlying disease genes in autism will require evaluation of hundreds of genetic markers spanning the genome and large sample sizes to obtain sufficient power to find underlying genes. In addition, limited fine mapping strategies will be employed in following up genome-wide linkage findings. The goals of this project continue to be to localize disease genes in autism through a systematic genome search, fine mapping, and candidate gene analysis. In a multi-site, international collaborative effort, 425 families with affected relative pairs with autism will be collected and genotyped on highly polymorphic markers spanning the human genome at regular, close intervals. The U.S. collaborative group will identify and phenotype and additional 100 families with affected siblings with autism and send blood from the families to U.K. for transformation of cell lines. The U.K.-European group of collaborators, through their own funding resources, will collect an additional set of 100 relative pairs and genotyping efforts will be conducted in an independent laboratory facility. Through this IMGSAC international collaborative effort, susceptibility genes can be identified in approximately 425 pairs. In addition, fine mapping studies will be performed in regions of interest, beginning with typing of thirty SNPs in the serotonin transporter gene (SLC6A4) region of interest from IMGSAC genome-wide scan in 250 trios consisting of a randomly chosen case type I from an IMGSAC family and their parents. The transmission disequilibrium test will then be performed, as well as Decay of Haplotype Sharing analysis. This project will continue to be actively involved in CPEA network-wide association analyses.